Vantage Snippets are short summaries of breaking news stories.
Yesterday’s publication of results from the Keynote-199 study in the Journal of Clinical Oncology will remind investors that prostate cancer is emerging as another tumour type amenable to checkpoint blockade. Keynote-199, a study of Merck & Co's Keytruda, segmented subjects by PD-L1 expression and bone metastasis, but remission rates were poor across the board. The few subjects who responded did so with unexpectedly long duration, a not atypical story in immunotherapy, and the best responses apparently came in those with DNA repair defects. It is interesting that of the immuno-oncology players only Merck has made a significant push into this cancer type, boasting in February of having started three pivotal Keytruda studies in various combinations, including with Parp inhibition (Esmo 2019 – A place for Parps in prostate cancer, September 30, 2019). However, only academic trials appear to focus specifically on prostate cancer driven by DNA repair defects. Bristol-Myers Squibb’s Opdivo trial Checkmate-7DX, somewhat analogous to Merck’s Keynote-921, and Roche’s Tecentriq study Imbassador-250 are the only other phase III tests under way. Other PD-(L)1-blocking agents are being studied in prostate cancer too, but these are largely investigator-sponsored efforts.
|Selected immunotherapy studies in prostate cancer|
|Trial||Setting & design||Enrolment|
|Keynote-641*||mCRPC, Xtandi combo, vs Xtandi||1,200|
|Keynote-921*||2L mCRPC, docetaxel combo, vs docetaxel||1,000|
|Keylynk-010*||3L mCRPC, Lynparza combo, vs Zytiga or Xtandi||780|
|Keylynk-007||HRRm &/or HRD+ve, Lynparza combo||300|
|Perseus-1**||≥2L mCRPC with high mutational load or DNA repair defect||100|
|Keynote-365||mCRPC, various combos||400|
|Checkmate-7DX*||Chemo-naive ≥2L mCRPC, docetaxel combo, vs docetaxel||984|
|Checkmate-650||mCRPC, Yervoy or Jevtana combo||618|
|Checkmate-9KD||mCRPC, Rubraca, docetaxel or Xtandi combo||330|
|ImmunoProst**||DNA repair defects||29|
|Imbassador-250*||3L mCRPC, Xtandi combo, vs Xtandi||771|
|NCT03821246**||Neoadjuvant, +/- Xtandi||51|
|NCT03810105**||HSPC, Lynparza combo||32|
|NCT02788773**||mCRPC, +/- tremelimumab||52|
|mCRPC=metastatic, castration-resistant prostate cancer; HRRm=homologous recombination repair mutation; HRD=homologous recombination deficiency; dMMR=mismatch repair deficient; HSPC=hormone-sensitive prostate cancer; *phase III; **investigator-sponsored. Source: clinicaltrials.gov.|
Only three weeks after Takeda announced encouraging 12-month results for its dengue vaccine TAK-003, the triumphalism appears to have waned, alongside the efficacy of the tetravalent injection. Longer 18-month results of the Tides study presented at the American Society of Tropical Medicine and Hygiene conference showed that the overall effectiveness of the vaccine had fallen from 80% to 73%. TAK-003’s ability to reduce hospitalisations also dropped, from 95% to 90%. But even more worrying is the project’s disappointing performance against the DENV-3 serotype, where it provided less than 50% protection. If this downward trend continues questions will be raised about its ability to provide protection against this serotype and the vaccine's safety, as infection with one serotype can raise the risk of severe illness when re-infected with another. For now TAK-003 is likely to remain the front runner in the developmental dengue field, following concerns about using Sanofi’s Dengvaxia in children who have not previously been infected with the virus. But the Tides study has another three years to run, and if TAK-003’s efficacy continues to fall across the serotypes its commercial potential could also wane. EvalutatePharma calculates 2024 consensus sales estimates of $453m.
|TAK-003 12-month and 18-month data|
|TIDES 12 mths||80%||74%||98%||63%||63%*|
|TIDES 18 mths||73%||70%||95%||49%||51%*|
|*Results inconclusive. Source: Tides study, published in NEJM; Takeda.|
Roche’s combination of Tecentriq with Avastin in the first-line hepatocellular cancer trial Imbrave-150 has allowed the Swiss group to succeed where Bristol-Myers Squibb failed. This is an important consideration as Roche fights to make Avastin the go-to half of an immunotherapy combo, and to keep this franchise relevant with doctors. While Bristol’s failed Checkmate-459 trial of Opdivo in the same setting has been criticised for enrolling a PD-L1-unselected population, Roche looks to have scored a resounding success in Imbrave-150, despite also not selecting PD-L1-positive subjects. That said, when the data were presented at a late-breaking session of the Esmo-Asia conference over the weekend no mention was made of PD-L1 positivity, so it is unclear to what extent PD-L1-positives might have driven the all-comers benefit. And it will not go unnoticed that 4.3 months of median progression-free survival for Imbrave-150’s Nexavar control cohort underperformed the 5.5 months cited on Nexavar’s US label. Nevertheless, Tecentriq plus Avastin now looks highly likely to become the first immunotherapy approved for first-line liver cancer, and to make life hard for the approved second-line agents Opdivo and Merck & Co’s Keytruda.
The smash hit Coapt study of Abbott Laboratories’ MitraClip mitral valve repair device has had far-reaching consequences, and not just for Abbott. So impressive was the device’s performance that the standard of care for mitral valve disease has changed, and this is the reason cited by Stifel analysts for Livanova’s decision to can development of Caisson, its prosthetic mitral valve. Livanova had acquired the device’s maker for $72m in 2017, presumably in an attempt to revive flagging sales at its valves business – a decline that is forecast to continue, according to EvaluateMedTech consensus. The group is restructuring its entire valve offering in a bid to boost profitability and eliminate overlap between production facilities. The 75 patients in Caisson’s European approval trial, Interlude, will continue to be followed for ethical reasons but the company said that “higher regulatory requirements” were one of the factors contributing to the restructuring; perhaps it believes the single-arm study would not be good enough to obtain CE mark. The shift will allow Livanova to prioritise faster growing areas, like treatment-resistant depression. Its Symmetry vagus nerve stimulator is in a trial called Recover in 1,000 refractory depression patients, aimed at obtaining Medicare coverage.
|WW annual sales ($m)|
|Autotransfusion machines and devices||91||82||-2%|
|Mechanical heart valves||39||31||-4%|
|Tissue heart valves||99||94||-1%|
|Other heart valves||9||9||-1%|
|Advanced circulatory support||44||91||+16%|
|Cardiac surgery total||873||991||+3%|
|Total company revenues||1,392||1,771||+5%|
|Note: Caisson is classed as a tissue valve. Source: EvaluateMedTech.|
Encouraging but early is surely the extent of the conclusions one can draw from Vertex and Crispr’s data today, in the first two patients to be treated with CTX001. The Crispr/Cas9 gene editing therapy is being studied in sickle cell and beta thalassaemia; two patients with severe cases of these diseases were infused earlier this year, and successfully achieved platelet engraftment. Four months after infusion the sickle cell subject was free from vaso-occuslive crises, while the beta thalassaemia patient was transfusion free nine months after; haemoglobin levels have risen markedly in both. The treatment was not free of toxicities, though serious adverse events were blamed on the busulfan conditioning and stem cell transplant procedures. Notably, Vertex struck a deal yesterday to search for novel conditioning regimes. CTX001 data had been expected to feature at the upcoming Ash conference, where instead the ability of Sangamo/Sanofi's ST-400 to challenge Bluebird's Lentiglobin will be the focus in sickle cell disease. Much more data are needed to assess CTX001's chances. Nevertheless, Crispr shares surged 23% in early trade, though with a market cap now close to $4bn and data in only two patients a takeover move by Vertex would be very surprising.
Novartis has won the race to get the first new-generation sickle cell treatment to market – but what does this mean for Global Blood Therapeutics? The US biotech's project voxelotor had been expected to have an edge over other sickle cell treatments as it aimed to address the underlying cause of the disease – Novartis’s Adakveo (crizanlizumab) only treats the painful vaso-occlusive crises sickle cell patients experience. But the benefits of voxelotor stimulating a haemoglobin response have been less than clear, and Adakveo has been approved on the hard endpoint of crises reduction. Novartis is to charge $85,000-113,000 a year for Adakveo, and says this could amount to annual sales of over $1bn, a figure significantly above current consensus sellside forecasts. The drug was approved two months before its original priority review action date, giving Novartis a first-mover advantage that should help it towards the blockbuster target. And the marketing weight of a pharma giant, compared with Global Blood’s go-it-alone strategy, might not only help Adakveo achieve its ambitions, but also neatly sideline its rival.
|Selected sickle cell projects|
|Project||Company||Mechanism of action||Status||2024e sales ($m)*|
|Adakveo (crizanlizumab)||Novartis||P-selectin antibody||Approved||331|
|Voxelotor||Global Blood Therapeutics||Sickle haemoglobin polymerisation inhibitor||Feb 2020 PDUFA date||1,575|
|Zynteglo/Lentiglobin||Bluebird Bio||Haemoglobin beta gene therapy||Phase III to start end 2019||604|
|CTX001||Vertex/Crispr Therapeutics||Crispr/Cas9 gene therapy||Phase I/II||277|
|*Sickle cell sales only. Source: EvaluatePharma.|
Four years of solid share price growth from Consort Medical came to an abrupt end this time last year, when demand fell for the inhaler used with partner Mylan's generic version of the asthma drug Advair; an explosion at one of its plants earlier this year only made matters worse. Presumably the UK company now believes that a full recovery will be a long time coming: it has tolday agreed to a buyout from Recipharm pitched at £10.10 per share, a 39% premium to Friday’s close but substantially below where the stock was trading for most of 2018. The private Swedish pharmaceutical manufacturer’s offer values Consort at £505m ($646m) or £626m including its debt. Recipharm’s opportunistic move is driven by a desire to grow its sales to SEK8bn ($817m) by 2020: Consort is forecast to have revenues of $386m that year, according to EvaluateMedTech’s sellside consensus. The pharmaceutical services sector has seen much consolidation in the past few years, so it was perhaps inevitable that a weakened Consort would fall prey to a bid; still, shareholders who remember the heady days of 2018 might be disappointed.
|Global sales ($m)|
|Bespak - drug delivery devices||161||166||183||201||+5%|
|Aesica - pharma CMO||209||220||234||248||+3%|
Vericiguat, the guanylate cyclase agonist on which Bayer and Merck & Co are collaborating, has flown under the radar, but perhaps for no longer. The phase III Victoria trial succeeded, the partners said today, showing a reduction in the risk of heart failure hospitalisation or cardiovascular death versus placebo in chronic heart failure with reduced ejection fraction (HFrEF). The actual numbers remain crucial: according to Bernstein analysts a 15-20% risk reduction on top of standard of care, Entresto, will need to be seen. A similar reduction in patients not taking Entresto might not be good enough; patients in Victoria were taking vericiguat on top of their normal heart failure therapies but it is not clear how many were on the Novartis drug. The project is not currently seen as a major future source of sales for either company - the partners share economics 50-50 - though another pending study should help assess the potential. The phase II Vitality trial has recruited patients with preserved ejection fraction (HFpEF), a much tougher setting, and is assessing whether vericuguat can improve physical functioning. Results are due early next year and another successful read out could prompt another look at this low profile asset.
|Vericiguat's forecast sales|
|WW annual sales ($m)|
|Merck & Co||Dec 2020||55||140||230||317|
Promedior’s sale for $390m to Roche today is notable for the fact that the biotech was to have been bought by someone else entirely. Four years ago Bristol-Myers Squibb had handed across $150m by way of an option to acquire Promedior, but that deal never reached fruition. Now Promedior can be doubly pleased: Roche has come in with even more money, and Bristol’s $150m has turned into a clean source of financing that sustained the private group for several years. Promedior’s lead, PRM-151, is a phase III-ready asset for idiopathic pulmonary fibrosis, a key area of interest for Roche, which had gained the IPF drug Esbriet through the $8.3bn takeout of Intermune in 2014. PRM-151 is a recombinant form of human pentraxin-2, a protein thought to prevent scarring, and Roche says it is the first project to show significant lung function improvements on top of current IPF therapies. It is in earlier trials for myelofibrosis, Nash and fibrotic kidney disease, and perhaps a recent long-term trial analysis persuaded Roche to pay up. Bristol, meanwhile, had an early presence in IPF via BMS-986020, but this project is no longer in active clinical trials.
|Second time lucky for Promedior|
|31 Aug 2015||Bristol-Myers Squibb||Pre phase 2||$150m option fee||$1.1bn in funding and exercise fees|
|15 Nov 2019||Roche||Pre phase 3||$390m up-front fee||$1.0bn contingent payments|
Kiadis’s move to scrap development of ATIR101 yesterday makes perfect sense given the regulatory roadblock that all three such stem cell transplant adjuncts have hit. But, even though Kiadis is moving to discontinue ATIR101’s phase III Hatcy study, it will not be able to draw a simple line under its troubles: subjects already enrolled into Hatcy must, for ethical reasons, be followed to completion. The study enrolled the first of 250 patients two years ago, and had been due to yield results in 2021. Kiadis had already bought the private NK cell therapy player Cytosen, and logically this business now becomes its key focus, with two assets, K-NK002 and K-NK003, to enter the clinic next year. But this brings up Kiadis’s next problem: with a share price off 85% year to date how does the group raise the necessary cash? Also in the doldrums is Kiadis’s peer company Bellicum, which had now effectively switched fully to Car-T work. However, its lead asset here, BPX-601, is progressing slowly, and the follow-up BPX-601 is having a hard time gaining US IND clearance.
|Stem cell transplant add-ons|
|Molmed||Zalmoxis||"No further investment"; phase III TK008 study closed to new enrolment||CD44v6 (Car-T), Car-NK & NGR-hTNF|
|Kiadis||ATIR101||Terminated; phase 3 Hatcy study being wound down||K-NK002 (HCST adjunct) & K-NK003 (undisclosed NK cell therapy)|
|Bellicum||BPX-501||Partner sought, and Bellicum activities "reduced"; phase III Thrive study recruiting||BPX-601 & BPX-603 (inducible Car-T)|
|Source: company websites.|